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Determinants of T Cell Fate in Transplantation Tolerance

移植耐受中 T 细胞命运的决定因素

基本信息

批准号：
10672382
负责人：
Mandy L Ford
金额：
$ 71.5万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672382
关键词：
Acceleration Acute Address Antibodies Apoptosis Attenuated Automobile Driving B-Lymphocytes CASP3 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Death Cell Separation Cells Clinical Clinical Trials Data Development Enzymes Equilibrium Exhibits Experimental Models FOXP3 gene Fc Receptor Fibrinogen Freedom Funding Gangliosides Gene Expression Profiling Goals Graft Rejection Grant Human Immune Immune system Immunity Immunologics Immunosuppression Immunotherapy Induction of Apoptosis Kidney Transplantation Knowledge Life Ligands Ligation Measures Mediating Memory Messenger RNA Metabolic Metabolism Modeling Molecular Mus Organ Organ Transplantation Outcome Paper Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Proteins Proteomics Receptor Signaling Regulation Regulatory Pathway Regulatory T-Lymphocyte Resistance Role Seminal Series Signal Pathway Signal Transduction Signaling Molecule Source Surface T cell response T memory cell T-Cell Activation T-Lymphocyte Tacrolimus Testing Therapeutic Therapeutic Intervention Transplant Recipients Transplantation Transplantation Tolerance Validation Waiting Lists Weaning allograft rejection clinically relevant cohort cytokine end-stage organ failure experimental study immune activation immunoregulation improved outcome in vivo isoimmunity kidney allograft mouse model nonhuman primate novel novel therapeutics patient population predictive marker receptor response retransplantation risk stratification skin allograft transcriptome sequencing translational study

项目摘要

Transplantation is a cure for end stage organ failure, yet achieving “one transplant for life” remains elusive for many transplant recipients due to immunologic rejection. Studies in mouse and NHP models and patient populations have consistently implicated memory CD8+ T cells as playing a causal role in mediating immunosuppression-resistant allograft rejection. Thus, the identification of the molecular mechanisms that regulate memory CD8+ T cells responses remains an important goal for immunotherapy in clinical transplantation. Fc receptors, previously known only to be expressed on B cells and innate immune cells, can fine-tune immune cell activation based on the balance of activating and inhibitory Fc receptor signaling, much like T cell costimulatory and coinhibitory molecules. During the last funding cycle we identified that the inhibitory receptor FcγRIIB is also expressed on a subset of multi-functional effector/ memory CD8+ T cells in mice and in humans, and showed that FcγRIIB functionally regulates CD8+ T cell immunity in a cell- autonomous manner in both mice and in a human clinical trial. However, the mechanisms by which this occurs are still not clear. First, the signals via which FcγRIIB ligation leads to T cell death are not known. We discovered that FcγRIIB signaling on CD8+ T cells is not controlled by antibody ligation, but instead by a novel immunosuppressive cytokine fibrinogen-like 2 (Fgl2). Moreover, our additional preliminary data suggest a FcγRIIB SHIP1-dependent mechanism that leads to the induction of apoptosis. Thus, in Aim 1, we will determine the cellular source of Fgl2 that is critical for FcγRIIB-mediated CD8+ T cell apoptosis, and will use a proteomics approach to elucidate the proximal intracellular signaling molecules that associate with FcγRIIB to promote caspase 3/7 activity. Second, we made the novel observation that FcγRIIB+ CD8+ T cells exhibit increased expression of the ganglioside metabolic enzyme Gm2a, and that increased expression of Gm2a mRNA in CD8+ T cells is associated with stability on minimal immunosuppression in a cohort of human renal transplant recipients. These preliminary data form the premise for the hypothesis to be tested in Aim 2: that Gm2a is a novel regulatory pathway that regulates transplant acceptance, potentially in an FcγRIIB- dependent fashion. Finally, in Aim 3 we propose to directly measure FcγRIIB, Fgl2, and Gm2a expression in CD8+ T cells isolated from a validation cohort of human renal transplant recipients, and to determine the association between CD8+ T cell FcγRIIB and Gm2a expression and reduced alloimmunity and/or acute rejection. These data will allow us to determine the ability of FcγRIIB/Gm2a-expressing T cells to be used as a predictive biomarker to stratify the risk of rejection following transplantation. In sum, through these mechanistic and translational studies, we will elucidate the fundamental molecular and cellular pathways of FcγRIIB- mediated inhibition of CD8+ T cell responses, and their therapeutic potential to attenuate memory CD8+ T cell responses and improve outcomes in clinical transplantation.

移植是治疗终末期器官衰竭的一种方法，但实现"一次移植终身"仍然是难以捉摸的，许多移植受者由于免疫排斥反应。在小鼠和NHP模型以及患者中的研究人群一直暗示记忆性CD8 + T细胞在介导免疫抑制抵抗性同种异体移植排斥。因此，确定的分子机制，调节记忆性CD8 + T细胞反应仍然是临床免疫治疗的重要目标。移植Fc受体以前只知道在B细胞和先天免疫细胞上表达，基于激活和抑制Fc受体信号传导的平衡，微调免疫细胞激活，如T细胞共刺激和共抑制分子。在上一个供资周期，我们确定，抑制性受体Fc γ RIIB也表达于小鼠中的多功能效应/记忆CD8 + T细胞亚群上。在小鼠和人类中，并显示Fc γ RIIB在功能上调节细胞中的CD8 + T细胞免疫。在小鼠和人类临床试验中以自主方式进行。然而，这种情况发生的机制还不清楚首先，Fc γ RIIB连接导致T细胞死亡的信号尚不清楚。我们发现CD8 + T细胞上的Fc γ RIIB信号传导不是由抗体连接控制的，而是由一种新的免疫抑制细胞因子纤维蛋白原样2（Fgl2）。此外，我们额外的初步数据表明， Fc γ RIIB依赖于SHIP1的机制导致细胞凋亡的诱导。因此，在目标1中，我们确定对Fc γ RIIB介导的CD8 + T细胞凋亡至关重要的Fgl2的细胞来源，和将使用蛋白质组学的方法来阐明近端细胞内信号分子， Fc γ RIIB促进胱天蛋白酶3/7活性。第二，我们发现Fc γ RIIB + CD8 + T细胞表现出神经节苷脂代谢酶Gm2a的表达增加， CD8 + T细胞中的GM2a mRNA与人类队列中最小免疫抑制的稳定性相关肾移植患者这些初步数据构成了目标2中检验假设的前提： Gm2a是一种新的调节途径，可以调节移植物的接受，可能存在于Fc γ RIIB中，依赖的方式。最后，在目标3中，我们提出直接测量Fc γ RIIB、Fgl2和Gm2a在小鼠中的表达。从人肾移植受者的验证队列中分离的CD8 + T细胞，并确定CD8 + T细胞在人肾移植受者中的表达。 CD8 + T细胞Fc γ RIIB和Gm2a表达与同种异体免疫和/或急性排斥反应这些数据将使我们能够确定表达Fc γ RIIB/Gm2a的T细胞用作免疫调节剂的能力。预测性生物标志物，以分层移植后排斥反应的风险。总之，通过这些机制，和翻译研究，我们将阐明Fc γ RIIB的基本分子和细胞途径，介导的CD8 + T细胞应答抑制，以及它们减弱记忆性CD8 + T细胞应答的治疗潜力改善临床移植的效果。